Chemical: Drug
desipramine

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Prescribing Info (1) Drug Labels (1) Clinical Annotations (5)

last updated 03/15/2017

1. Annotation of CPIC Guideline for desipramine and CYP2D6

Summary

Tricyclic antidepressants have comparable pharmacokinetic properties, it may be reasonable to apply the CPIC Dosing Guideline for amitriptyline/nortriptyline and CYP2C19, CYP2D6 to other tricyclics including desipramine. The CPIC Dosing Guideline update for nortriptyline recommends a 25% dose reduction for CYP2D6 intermediate metabolizers. For CYP2D6 ultrarapid or poor metabolizers, an alternative drug should be considered. If nortriptyline is warranted, consider a 50% dose reduction in CYP2D6 poor metabolizers.

Annotation

This annotation is based on the CPIC® guideline for tricyclic antidepressants and CYP2D6 and CYP2C19.

December 2016 Update

Advance online publication December 2016.

The 2016 update of CPIC guidelines regarding the use of pharmacogenomic tests in dosing of tricyclic antidepressants (TCAs) have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature up to July 2016 was reviewed, recommendations and supplemental information were updated.
Excerpt from the 2016 dosing guideline update:
- "Both amitriptyline and nortriptyline are used as representative TCAs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. However, the results of these studies may apply to other TCAs because these drugs have comparable pharmacokinetic properties."
- "There is substantial evidence linking CYP2D6 genotypes to phenotypic variability in tricyclic side-effect and pharmacokinetic profiles. Modifying pharmacotherapy for patients who have CYP2D6 genomic variants that affect drug efficacy and safety could potentially improve clinical outcomes and reduce the failure rate of initial treatment."
- " There are scarce studies focusing solely on CYP2D6 genotype and association with pharmacokinetic parameters or treatment outcomes of TCAs in pediatric patients. CYP2D6 activity is fully mature by early childhood, but CYP2C19 activity may be increased in children relative to adults. Although further genomic ontogeny studies are needed, there is a lack of evidence suggesting that this guideline cannot be extrapolated to pediatric patients."
The guideline includes dosing recommendation for TCAs based on:
- CYP2D6 phenotype (Table 1 below)
Download and read:

Table 1: Dosing recommendations for TCAs based on CYP2D6 phenotype:

Adapted from Tables 1 and 2 of the 2016 guideline update.

Likely phenotype	Activity score	Genotypes	Examples of diplotypes	Implications	Therapeutic Recommendations^{a, b}	Classification of recommendation for other TCAs ^c
CYP2D6 Ultrarapid metabolizer (~1-20% of patients)^d	>2.0	An individual carrying more than two copies of functional alleles	1/1xN, 1/2xN	Increased metabolism of TCAs to less active compounds compared to normal metabolizers. Lower plasma concentrations of active drug will increase probability of pharmacotherapy failure.	Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments.^e	Optional
CYP2D6 Normal metabolizer (~72-88% of patients)^d	1.0-2.0^f	An individual carrying two normal function alleles or two decreased function alleles or one normal and no function allele or one normal and decreased function allele or combinations of duplicated alleles that result in an activity score of 1.0-2.0	1/1, 1/2, 2/2, 1/9, 1/41, 41/41, 1/4, 1/5	Normal metabolism of TCAs.	Initiate therapy with recommended starting dose.^g	Strong
CYP2D6 Intermediate metabolizer (~1-13% of patients)^d	0.5	An individual carrying one decreased and one no function allele	4/41, 5/9, 4/10	Reduced metabolism of TCAs to less active compounds when compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.	Consider 25% reduction of recommended starting dose.^g Utilize therapeutic drug monitoring to guide dose adjustments.^e	Optional
CYP2D6 Poor metabolizer (~1-10% of patients)^d	0	An individual carrying only no function alleles	4/4, 4/4xN, 3/4, 5/5, 5/6	Greatly reduced metabolism of TCAs to less active compounds compared to normal metabolizers. Higher plasma concentrations of active drug will increase the probability of side effects.	Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider 50% reduction of recommended starting dose.^g Utilize therapeutic drug monitoring to guide dose adjustments.^e	Optional

^a For tertiary amines (e.g., amitriptyline), if CYP2C19 genotype results are also available, see Table 2 for CYP2C19-based dosing recommendations and Table 3 below for CYP2D6/CYP2C19-based dosing recommendations.

^b Dosing recommendations only apply to higher initial doses of TCAs for treatment of conditions such as depression. See other considerations in the guideline for dosing recommendations for conditions where lower initial doses are used, such as neuropathic pain.

^c The rating scheme for the recommendation of classification is described in the Supplement. It may be reasonable to apply amitriptyline recommendation to other TCAs also metabolized by CYP2D6 including clomipramine, desipramine, doxepin, imipramine, and trimipramine. There are fewer clinical and pharmacokinetic data supporting genotype-guided dose adjustments for these drugs when compared to amitriptyline or nortriptyline (Supplemental Tables S8-S16).

^d CYP2D6 metabolizer status frequencies are based on average multi-ethnic frequencies. See the CYP2D6 Frequency Tables for population-specific allele and phenotype frequencies.

^e Titrate dose to observed clinical response with symptom improvement and minimal (if any) side effects.

^f Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

^g Patients may receive an initial low dose of a tricyclic, which is then increased over several days to the recommended steady-state dose. The starting dose in this guideline refers to the recommended steady-state dose.

May 2013

Guidelines regarding the use of pharmacogenomic tests in dosing for tricyclic antidepressants have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Download: article and supplement

Excerpt from the dosing guidelines:

Amitriptyline and nortriptyline are used as model drugs for this guideline because the majority of pharmacogenomic studies have focused on these two drugs. Because the tricyclics have comparable pharmacokinetic properties, it may be reasonable to apply this guideline to other tricyclics including clomipramine (Supplementary Table S15), with the acknowledgement that there are fewer data supporting dose adjustments for these drugs than for amitriptyline or nortriptyline.

See nortriptylinefor excerpts and tables that summarize CYP2D6-based and CYP2C19-based dosing recommendations for amitriptyline when higher initial starting doses are warranted (article).

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last updated 10/25/2013

1. Annotation of FDA Label for desipramine and CYP2D6

On FDA Biomarker List

Actionable PGx

Summary

The FDA-approved drug label for desipramine (NORPRAMIN) notes that CYP2D6 poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs), such as desipramine, when given typical doses. Additionally, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. It is therefore desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be a CYP2D6 inhibitor.

Annotation

Desipramine (NORPRAMIN) is an antidepressant drug belonging to the tricyclic antidepressants class.The FDA-approved drug label for desipramine highlights information regarding CYP2D6 poor metabolizers, as well as information about usage of drugs that inhibit CYP2D6, one of the enzymes responsible for desipramine metabolism.

Excerpt from the desipramine (NORPRAMIN) label:

The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6...is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers...It is desirable to monitor TCA plasma levels whenever a TCA including is going to be co-administered with another drug known to be an inhibitor of P450 2D6.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the desipramine drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

Depression
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depressive Disorder
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
Depressive Disorder, Major
- Indications & usage section, Warnings section, Adverse reactions section, Precautions section
- source: PHONT
CYP2D6
- metabolism/PK, Precautions section
- source: U.S. Food and Drug Administration

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.